Methods for the prevention and/or the treatment of glutamate cytotoxicity

ABSTRACT

The present invention relates to the use of beta-naphthoquinone derivatives, and salts thereof, for the prevention and/or the treatment of glutamate cytotoxicity. It further relates to the use of beta-naphthoquinone derivatives, and salts thereof, for preventing and/or treating glutamate induced neurological disorders. Additionally, it concerns the use of beta-naphthoquinone derivatives, and salts thereof, for making drugs exerting an inhibitory effect on the release of glutamate.

The present invention relates to the use of beta-naphthoquinonederivatives, and salts thereof, for the prevention and/or the treatmentof glutamate cytotoxicity. It further relates to the use ofbeta-naphthoquinone derivatives, and salts thereof, for preventingand/or treating glutamate induced neurological disorders. Additionally,it concerns the use of beta-naphthoquinone derivatives, and saltsthereof, for making drugs exerting an inhibitory effect on the releaseof glutamate.

A large number of studies have established that cellular communicationusing excitatory amino acids can be transformed into a mechanism of celldestruction.

Glutamate is the main excitatory neurotransmitter in the nervous system,especially brain and spinal cord, of mammals wherein it is working at avariety of excitatory synapses.

The ubiquitous distribution of glutamate receptors throughout thenervous system proves that glutamate plays a central role in a widerange of physiological as well as pathological events (Watkins J. C.,Collingridge G. L., The NMDA receptor, IRL Oxford, 1989). It is forexample strongly suggested that it plays a central role in functionssuch as learning, pattern recognition, and memory (Bliss T. V. P.Collingridge G. L., Nature 361, 31-39, 1993).

Normally extracellular levels of glutamate are elevated only in a briefand spatially localized fashion associated with normal synaptictransmission however, under pathologic circumstances levels may remaindramatically increased.

Additionally, it has also been known for decades that glutamate is toxicto neurons in vitro and in vivo and that the function of glutamatereceptor, especially glutamate receptors of the N-methyl-D-aspartate(“NMDA”) receptor subtype, is crucial in a number of neuronal damagesand injuries (Appel S. H., Trends Neurosci. 16, 3-5, 1993). Manyneurological disorders involving epileptic seizures and chronic or acutedegenerative processes, such as for example Alzheimer's, Huntington's,Parkinson's diseases, multiple sclerosis (MS), amyotrophic lateralsclerosis (ALS), spinal muscular atrophy (SMA), retinopathy, stroke andtraumatic brain injury, involve neuronal cell death caused byover-stimulation of the glutamate receptors. Similarly, it has beenshown that neuronal injury caused by ischemia after occlusion ofcerebral arteries could, at least partially, be mediated by excessiveactivation of glutamate receptors as in the ischemic brain,extracellular glutamate is elevated rapidly after the onset of ischemiaand declines following reperfusion (Davalos et al., 1997, Stroke, 28,708-710). Other pathologic circumstances associated with dramaticincrease of extracellular glutamate levels are hypoxia or hypoglycaemia.Finally, Stephans and Yamamoto (1994, Synapse, 17, 203-209) have shownthat drug-induced neurotoxicity, for example neurotoxic effects ofmethamphetamine (METH) on striatal dopaminergic neurons, could actuallybe mediated by over-stimulation of the glutamate receptors.

These excessive activations of glutamate receptors, referred to as“glutamate cytotoxicity”, are actually associated with the elevation ofextracellular glutamate levels. The mechanisms of the elevation ofextracellular glutamate include enhanced efflux of glutamate and/or thereduction of glutamate uptake by cells. Thus, it would be desirable toprovide a means of protecting affected cells, especially neurons, fromglutamate-induced cytotoxicity, and more specifically to provide meansof regulating glutamate release and/or uptake by glutamate producingcells.

To this end, it has already been proposed to target the glutamatereceptors, mostly the N-methyl-D-aspartate (“NMDA”) receptor, present onthe targeted cells by inhibiting them by the use of agonist orantagonist specific molecules. Examples of such molecules areanthranilic acid derivatives (see U.S. Pat. No. 5,789,444), Basilen BlueD-3G (Reactive Blue 2) and Cibacron Blue 3GA and5-adenylylimidodiphosphate (AMPPNP) (see U.S. Pat. No. 6,326,370), NMDAspecific antagonists such as ketamine, dextromophan, or3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (Kristensen et al.,1992, Pain, 51:249-253; Eide et al., 1995, Pain, 61, 221-228), or the2-methyl-6-(phenylethynyl)pyridine (MPEP) which is an antagonist of themetabotropic glutamate receptor subtype 5 (mGluR5) (Ossowska et al.,2001, Neuropharmacology,41, 413-420).

However, widespread use of these compounds is precluded by theirundesirable side effects (e.g. psychotomimetic effects, headache,hallucinations, dysphoria or disturbances of cognitive and motorfunctions). Thus, the available treatment methods are not satisfactoryin terms of safety or efficiency for their wide implementation.

Therefore, there is still a need in the provision of improved methodsand means for protecting affected cells, and more preferably neurons,from glutamate-induced cytotoxicity.

The investigation by the inventors has now surprisingly shown thatcertain beta-naphthoquinone derivative compounds, previously used asvasoprotective drugs, have preventing and/or treating effects onglutamate-induced cytotoxicity. More specifically, said compounds havebeen shown to control, and preferably inhibit, the spontaneous and/orthe evoked (i.e. the glutamate release by cells in response todepolarization) release of glutamate.

Thus the present invention provides a new class of compounds whichrepresents a pharmacological alternative to previously describedcompounds, such as competitive and non-competitive glutamate antagonistsor agonists, gangliosides and growth factors, for the treatment orprevention of acute and chronic glutamate-related diseases orconditions, particularly neurological diseases. In preferredembodiments, the present invention provides a new class of compoundswhich can be used as pharmacological tools for the modulation ofglutamate cellular release and cytotoxicity, preferably neurotoxicity,and which allows the possible treatment and/or prevention of manyneurological disorders involving epileptic seizures and acute andchronic neurodegenerative diseases, as well as neuronal injury caused byischemia or glutamate-related diseases or conditions, wherein saiddisorders are, at least partially, associated with excessive activationof glutamate receptors and/or with excessive extracellular glutamatelevels.

The invention is therefore first directed to a novel use ofbeta-naphthoquinone derivatives for making drugs with an inhibitoryeffect on the extracellular glutamate release, wherein said derivativesare selected among the group consisting of:

-   -   (i) compounds having the formula (I)    -   wherein R represents —NH—CO—NH₂, —NH—CO—CH₃, or —OH group,    -   (ii) glucuronide derivatives thereof having the formula (II):        wherein R is as above indicated, and    -   (iii) addition salts thereof.

According to preferred embodiments, said derivatives are selected amongthe group consisting of the 1,2-naphthoquinone, 2-semicarbazone, alsocalled naftazone according to its international common name, and itscorresponding glucuronidated derivative, i.e. the1-(1-hydroxy,2-naphthyl)semicarbazide-1-β-O-gluco-pyranosiduronic acid,respectively of formula (III) and formula (IV):

In special embodiment, the derivatives of the invention are furthersubstituted with, one to four, identical or different, heteroatomsand/or hetero groups. Examples of said heteroatoms and/or hetero groupsare O, H, alkyl groups C_(n)H_(n+1), with n=1 to 5, OCH₃, N, halogens(for example F or Br), S or any labeling element allowing to visualizesaid derivatives. These substituting atoms or groups, and their uses,are widely known in the art.

The addition salts of the derivatives of the invention compriseconventional salt formed from inorganic or organic acids or bases, suchas hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, perchloric,fumaric, acetic, sodium, lithium, potassium, magnesium, aluminium,calcium, zinc, ethylenediamine ; formic, benzoic, maleic, tartaric,citric, oxalic, aspartic acid, and alkane-sulfonic acids is evenmentioned.

The preparation of compounds used according to the invention has beenwidely described in the literature, for example, in BSM 924 M or PatentFR 2103 504.

The newly identified inhibitory properties of these compounds, reportedin the examples hereafter, make them particularly suitable for treatingand/or preventing diseases, conditions and attacks related todeleterious effects of glutamate released in exess, and preferablyneurological ones.

Thus the present invention further relates to a method for treatingand/or preventing glutamate-evoked cytotoxicity in a patient in needthereof comprising administering to said patient a compositioncontaining a therapeutically effective amount of at least onebeta-naphthoquinone derivative and a pharmaceutically acceptablecarrier, wherein said derivative is selected among the group consistingof :

-   -   (i) compounds having the formula (I):        wherein R represents —NH—CO—NH₂, —NH—CO—CH₃, or —OH group, and    -   (ii) glucuronide derivatives thereof having the formula (II):        wherein R is as above indicated, and    -   (iii) addition salts thereof.

In preferred embodiments, the derivatives administered according to themethod of the invention are selected among the group consisting of the1,2-naphthoquinone, 2-semicarbazone, also called naftazone, and itscorresponding glucuronidated derivative, i.e. the1-(1-hydroxy,2-naphthyl)semicarbazide-1-β-O-gluco-pyranosiduronic acid(see formula (III) and (IV) respectively). Similarly, these derivativesmight be substituted with, one to four, identical or different,heteroatoms and/or hetero groups as defined above.

The term “glutamate-evoked cytotoxicity” within the present invention isintended to designate cell toxicity associated with excessiveactivations of glutamate receptors. These terms are well known by theone skilled in the art. More specifically, the “glutamate-evokedcytotoxicity” concerns all affected cells expressing glutamatereceptors. According to preferred embodiments, these affected cells arenervous cells (i.e. neuro-cells), preferably neurons. These affectednervous cells are, for example, present in brain, spinal cord, retina,at the neuro-muscular junction, etc . . . “Cytotoxicity” means that thecell functions and/or properties are affected, leading to cellmalfunctioning, and finally to cell death.

In a particularly preferred embodiment, the method of the invention isintended for treating and/or preventing glutamate-evoked neurotoxicity,and even more preferably for treating and/or preventingneurodegeneration (i.e. degeneration of nervous cells).

The present invention further relates to a method for modulating therelease of glutamate in a patient comprising administering to saidpatient a composition containing a therapeutically effective amount ofat least one beta-naphthoquinone derivative and a pharmaceuticallyacceptable carrier, wherein said derivative is selected among the groupconsisting of derivatives of Formula I to IV, and addition saltsthereof. These derivatives are detailed above. “Modulating the releaseof glutamate” means that the levels of released glutamate in non treatedpatient is different from the one observed after his treatment with thederivatives of the invention. According to preferred embodiment,treatment of the patient with the derivatives of the invention leads toa negative modulation, preferably to the inhibition, of the glutamaterelease by the producing cells, and thus to a decreased glutamate levelin the treated patient compared to the glutamate level observed beforesaid treatment.

The present invention further relates to a method for treating and/orpreventing disease and/or condition associated with the excessiverelease of glutamate in a patient comprising administration to saidpatient of a composition containing a therapeutically effective amountof at least one beta-naphtoquinone derivative and a pharmaceuticallyacceptable carrier, wherein said derivative is selected among the groupconsisting of derivatives of Formula I to IV, and addition saltsthereof. These derivatives are detailed above.

“Disease and/or condition associated with the excessive release ofglutamate” is intended to designate large number of acute and chronicglutamate-related diseases or conditions, particularly neurologicaldiseases. It designates more specifically epileptic seizures and acuteand chronic neurodegenerative diseases, as well as neuronal injurycaused by ischemia or glutamate-related diseases or conditions, whereinsaid disorders are, at least partially, associated with excessiveactivation of glutamate receptors and/or with excessive extracellularglutamate levels. Examples are involving chronic or acute degenerativedisorders, such as for example Alzheimer's, Huntington's, Parkinson'sdiseases, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS),spinal muscular atrophy (SMA), retinopathy, stroke and traumatic braininjury, involve neuronal cell death caused by over-stimulation of theglutamate receptors. Similarly, neuronal injury caused by ischemia ordrug-induced neurotoxicity, for example neurotoxic effects ofmethamphetamine (METH) on striatal dopaminergic neurons, are indicationsof the methods according to the present invention. Other indications areglutamate-related conditions such as for example pain, hormonal balance,blood pressure, thermoregulation, respiration, learning, patternrecognition or memory, or any disorder subsequent to hypoxia orhypoglycaemia.

For example, the treatment of epilepsy, amyothrophic lateral sclerosis,spinal muscular atrophy (SMA), Huntington's disease, deleterious effectdue to excesses of glutamate released as a result of cerebral accidentsof traumatic or other vascular origin will be mentioned.

The derivatives described herein are administered as a compositioncontaining at least one active compound and a pharmaceuticallyacceptable carrier. In preparing such a composition, any conventionalpharmaceutically acceptable carrier can be utilized. The carriermaterial can be an organic or inorganic inert carrier material suitablefor the selected route of administration. Suitable carriers includewater, gelatin, gum arabic, lactose, starch, magnesium stearate, talc,vegetable oils, polyalkylene-glycols, petroleum jelly and the like.Furthermore, the pharmaceutical composition may contain otherpharmaceutically active agents. Additional additives such as flavoringagents, preservatives, stabilizers, emulsifying agents, salts forvarying the osmotic pressure, buffers and the like may be added inaccordance with accepted practices of pharmaceutical compounding. Anyconventional form such as tablets, capsules, pills, powders, granules,and the like may be used. Advantageously, they are in the form oftablets, sugar coated tablets, hard gelatin capsules, capsules,granules, for oral administration, or solutions or suspensions foradministration via an injectable channel.

The methods of the invention may be carried out by administering thecomposition containing derivative of the invention by any route wherebydrugs are conventionally administered. Such routes include systemic andlocal routes. Examples are intravenous, intramuscular, subcutaneous,intracranial, intraperitoneal, as well as oral routes. Preferably, themethod of the invention is carried out via oral or intravenous routes ofadministration.

In accordance with this invention, the derivatives described herein areuseful in pharmaceutically acceptable oral modes. A preferred oraldosage form comprises tablets, capsules of hard or soft gelatin,methylcellulose or of another suitable material easily dissolved in thedigestive tract. The oral dosages contemplated in accordance with thepresent invention will vary in accordance with the needs of theindividual patient as determined by the prescribing physician. Thepreferred oral dosage form is capsules or tablets containing from 50 to500 mg of a derivative of the invention.

Typical preparations for intravenous administration would be sterileaqueous solutions including water/buffered solutions. Intravenousvehicles include fluid, nutrient and electrolyte replenishers.Preservatives and other additives may also be present such asantibiotics and antioxidants. Compositions for bolus i.v. administrationmay contain up to 10 mg/ml (10,000 mg/liter) of derivative describedherein. Compositions for i.v. administration preferably contain fromabout 50 mg/liter to about 500 mg/liter of at least one derivativedescribed herein.

In carrying out the method of the invention, derivative of the inventionis generally given to adults daily, preferably orally or intravenously,in an amount of from about 5 mg/kg to about 30 mg/kg daily, in single ordivided doses, preferably from about 13 mg/kg to about 17 mg/kg daily,with the precise dosage being varied depending upon the needs of thepatient. The doses will be adapted according to the patient and thepathology to be treated and are for example 1 mg-100 mg/day. In general,this therapy is carried out for a period of about three months.Alternatively, the method of the invention may be carried outprophylactically for an indefinite time in those patients who are have ahigh risk of suffering an acute neurotoxic event, such as a stroke. Forthe treatment of an acute neurotoxic event, the patient should betreated in accordance with the method of the invention as soon aspossible after the diagnosis of the acute neurotoxic event, preferablywithin twelve hours, and most preferably within six hours, of the onsetof the neurotoxic event. When the drug is administered orally, it isgenerally administered at regular intervals.

These drugs are notably administered orally or via an injectablechannel.

The invention has been described in an illustrative manner, and it is tobe understood that the terminology which has been used is intended to bein the nature of words of description rather than of limitation.Obviously, many modifications and variations of the present inventionare possible in light of the above teachings. It is therefore to beunderstood that within the scope of the claims, the invention may bepracticed otherwise than as specifically described.

All of the above cited disclosures of patents, publications and databaseentries are specifically incorporated herein by reference in theirentirety to the same extent as if each such individual patent,publication or entry were specifically and individually indicated to beincorporated by reference.

Examples below, demonstrate that the beta-naphthoquinone derivativesdescribed herein inhibit both the spontaneous and evoked-release ofglutamate.

Other features and advantages of the invention are given in thefollowing examples, wherein reference is made to FIGS. 1 and 2, whereinrespectively:

FIG. 1 represents the diagram illustrating the chemiluminescencemeasurement protocol, and

FIG. 2 represents the spontaneous release of glutamate and the inducedone versus the concentration of naftazone (FIG. 2A) or of itsglucuronidated derivative (FIG. 2B).

EXAMPLE 1 Study of the Inhibitory Effects on Glutamate by Naftazone andits Glucuronidated Derivative

A: Study of the effect of a continuous treatment with naftazone for 15days on the glutamate levels in the CSF (cerebrospinal fluid) of normalrats Sprague-Dawley rats weighing 200-220 g and Swiss-Webster mice ofboth sexes, aged 4-8 weeks, are used.

The animals are kept in cages, in a well-ventilated room at 23-24° C.,with a light/darkness cycle of 12 hours.

In order to investigate the CSF glutamate levels in the controls, orafter treatment with naftazone, the male rats are divided into 3 groups:

-   -   Group I (n=8) is used as control. The rats of this group are fed        per os for 15 days with the same carrier as the one used for        solubilizing naftazone, i.e. 1% methylcellulose Sigma,    -   The animals of groups II (n=5) and III (n=5) are fed per os for        15 days with 10 and 100 mg of naftazone per kg, per day,        respectively, given as a single bolus.

The CSF of anesthetized rats with 6% pentobarbital (i.p.) is collectedby operating according to the usual procedures.

The animals are then decapitated. The CSF samples are centrifuged at6,000 g for 10 min at 10° C.

The supernatant is extracted, the sediment containing the blood depositsis removed.

The samples are held in 2.5% trichloracetic acid and kept at −80° C.

Ether is used for washing trichloracetic acid off the samples.

In order to determine the glutamate levels in the CSF, chemiluminescencemeasurements are conducted according to the procedure described in thediagram given in FIG. 1. The reaction is based on the oxidization ofglutamate into 2-oxoglutarate under the action of glutamatedehydrogenase, which produces NaDH2, evaluated by using thechemiluminescent reaction of photobacterium.

The CSF samples are tested by adding a known volume of sample to thereaction medium which contains 250 μl of saccharose (120 mM) in Trisbuffer (120 mM, pH 7.2), 50 μl of an enzymatic mixture of NAD, DMN,NADH-FMN oxidoreductase, luciferase and GDH, and 5 μl of n-decylaldehyde.

The light emitted by the luminescent reaction consecutive to theoxidization of L-glutamate and to the production of NADH, is detected bya photomultiplier unit, recorded and calibrated by comparing it withlight emitted by a glutamate standard.

Statistical analysis of the data is carried out by using Student's ttest for unpaired samples. The values are expressed as average +/−SEM,n=number of animals or experiments carried out.

The data are considered as significantly different from the controls, atp<0.05.

The control rats (Group I) which have received the methylcellulosecarrier for 15 days, have a CSF glutamate content from 16-34 nmol ml⁻¹with an average value of 22.1 +/−6.3 nmol ml⁻¹ (n=8).

The daily treatment of rats (groups II and III) for 15 days with anaftazone dose of 10 or 100 mg/kg show that the CSF glutamate content inboth groups of rats is 8.1 +/−1.8 (n=5) and 10.8 +/−3.3 ml⁻¹ (n=5),respectively.

These results show that the glutamate content in the CSF of rats treatedwith both naftazone doses is significantly reduced (p=0.001 and p=0.004,respectively), as compared with the controls.

Furthermore, no significant difference in CSF glutamate content isobserved between both groups of rats treated with naftazone, which showsthat the effect of the drug is not dose-dependent.

B: Study of the effect of naftazone and of its glucuronide derivativeson the release of glutamate from synaptosomes of mouse brains.

In order to prepare the synaptosomes of mossy fibers, the Swiss-Websterrats are decapitated and the cerebellum is rapidly removed. Small piecesof tissue (1-2 mm³) are washed in 100 ml of a mammal saline standardsolution containing (mM): NaCl, 136; KCl, 5.6; MgCl₂ 1.2; CaCl₂ 2.2;glucose 5.5; NaHCO₃ 7.5; NaHPO₄/Na₂HPO₄ buffer 1.2.

An oxygen current is caused to flow through them for 10 minutes.

In order to dissociate the pieces, they are sucked in a reciprocalmovement with a 1 ml pipette.

The homogenate obtained is diluted in 3 ml of mammal Krebs's solutionand is filtered through a Nylon® tissue (mesh 50 μm).

The filtrate is collected and left to settle for 30-45 min by gravity.

Synaptosomes derived from the glutamatergic mossy fibers settle becauseof their large size with the nuclear fraction. The supernatant isdiscarded and the sediment is resuspended in 1 ml of a standardsolution. The release of glutamate from the synaptosomes is detectedaccording to the technique used for evaluating it in the CSF.

FIGS. 2A and 2B show the effects of naftazone (at concentrations of0.5-50 μM) and of its glucuronidated derivative, respectively, on thespontaneous release of glutamate (curve -∘-) and of that induced bydepolarization (curve -•-) Each point in A and B represents the ISEMaverage of 3 measurements carried out in triple. In A, the spontaneouslyreleased glutamate is continuously measured during an exposure of 1 hourto the tested drug and is compared with controls. Release of glutamateby depolarization is determined after a 1 hour exposure to the testeddrug and is compared with controls.

The drugs are left to incubate for 1 hour with synaptosomal aliquotsbefore the measurement.

The release of glutamate in response to the depolarization induced by amedium with a high K⁺ content (30 mM) containing Ca²⁺ (5 mM) is notsignificantly affected by naftazone at the investigated concentrationvalues.

However, as FIG. 2A shows, naftazone reduces the spontaneous release ofglutamate from synaptosomes. The inhibitory effect of naftazone on thespontaneous release of glutamate is already observed at the lowestconcentration of drug used (0.5 μM). This effect is maximal at theconcentration of 25 μM.

Higher concentrations do not seem to further increase the inhibitoryeffect.

When the effect of the glucuronidated derivative on the spontaneousrelease and on that caused by K⁺ is evaluated, it is seen that the drugdoes not reduce the spontaneous release of glutamate in the range of theconcentrations used.

However, as FIG. 2B shows, the glucuronidated derivative reduces, in adose-dependent way, the release induced by a medium with a high K⁺content (20 mM) containing Ca²⁺ (5 mM).

The maximum reduction (about 60%) is observed at the highestconcentration of the tested drug (32 μM).

EXAMPLE 2 Manufacture of Pharmaceutical Compositions

By operating according to the conventional techniques, tablets are madecontaining:

-   -   naftazone: 10 mg    -   excipient qsp for 100 mg or injectable solutes containing:    -   naftazone: 5 mg    -   sterile water qsp: 2 ml.

1. A method for treating and/or preventing glutamate-evoked cytotoxicityin a patient in need thereof comprising administering to said patient acomposition containing a therapeutically effective amount of at leastone beta-naphthoquinone derivative and a pharmaceutically acceptablecarrier, wherein said derivative is selected among the group consistingof: (i) compounds having the formula (I):

wherein R represents —NH—CO—NH₂, —NH—CO—CH₃, or —OH group, and (ii)glucuronide derivatives thereof having the formula (II):

wherein R is as indicated in (i), and (iii) addition salts thereof. 2.The method of claim 1, wherein said derivative is selected among thegroup consisting of the 1,2-naphthoquinone, 2-semicarbazone and the1-(1-hydroxy,2-naphthyl)semicarbazide-1-β-O-gluco-pyranosiduronic acid.3. The method of claim 1, wherein said glutamate-evoked cytotoxicity isa glutamate-evoked neurotoxicity.
 4. The method of claim 1, wherein saidglutamate-evoked cytotoxicity is neurodegeneration.
 5. A method formodulating the release of glutamate in a patient comprisingadministering to said patient a composition containing a therapeuticallyeffective amount of at least one beta-naphthoquinone derivative and apharmaceutically acceptable carrier, wherein said derivative is selectedamong the group consisting of: (i) compounds having the formula (I):

wherein R represents —NH—CO—NH₂, —NH—CO—CH₃, or —OH group, (ii)glucuronide derivatives thereof having the formula (II):

wherein R is as indicated in (i), and (iv) addition salts thereof. 6.The method of claim 5, wherein said derivative is selected among thegroup consisting of the 1,2-naphthoquinone, 2-semicarbazone and the1-(1-hydroxy,2-naphthyl)semicarbazide-1-β-O-gluco-pyranosiduronic acid.7. A method for inhibiting the release of glutamate in a patientcomprising administering to said patient a composition containing atherapeutically effective amount of at least one beta-naphthoquinonederivative and a pharmaceutically acceptable carrier, wherein saidderivative is selected among the group consisting of: (i) compoundshaving the formula (I):

wherein R represents —NH—CO—NH₂, —NH—CO—CH₃, or —OH group, (ii)glucuronide derivatives thereof having the formula (II):

wherein R is as indicated in (i), and (v) addition salts thereof.
 8. Themethod of claim 7, wherein said derivative is selected among the groupconsisting of the 1,2-naphthoquinone, 2-semicarbazone and the1-(1-hydroxy,2-naphthyl)semicarbazide-1-β-O-gluco-pyranosiduronic acid.9. A method for treating and/or preventing disease and/or conditionassociated with the excessive release of glutamate in a patientcomprising administration to said patient of a composition containing atherapeutically effective amount of at least one beta-naphthoquinonederivative and a pharmaceutically acceptable carrier, wherein saidderivative is selected among the group consisting of: (i) compoundshaving the formula (I):

wherein R represents —NH—CO—NH₂, —NH—CO—CH₃, or —OH group, (ii)glucuronide derivatives thereof having the formula (II):

wherein R is as indicated in (i), and (iii) addition salts thereof. 10.The method of claim 9, wherein said derivative is selected among thegroup consisting of the 1,2-naphthoquinone, 2-semicarbazone and the1-(1-hydroxy,2-naphthyl)semicarbazide-1-β-O-gluco-pyranosiduronic acid.11. The method of claim 10, wherein said disease and/or conditionassociated with the excessive release of glutamate is selected among thegroup consisting of epileptic seizures, acute and chronicneurodegenerative diseases, ischemia, Alzheimer's, Huntington's,Parkinson's diseases, multiple sclerosis (MS), amyotrophic lateralsclerosis (ALS), spinal muscular atrophy (SMA), retinopathy, stroke andtraumatic brain injury, drug-induced neurotoxicity, pain, hormonalbalance, blood pressure, thermoregulation, respiration, learning,pattern recognition, memory, and disorders subsequent to hypoxia orhypoglycaemia.